Molecular Sequelae of Myeloma-Bone Marrow Interactions: Therapeutic Applications We have defined the molecular mechanisms whereby interactions of multiple myeloma (MM) cells with BM stromal cells (BMSCs) mediate growth, survival, migration, and drug resistance in the BM milieu using in vitro and in vivo models. We have then validated novel therapeutics targeting the MM cell and its BM microenvironment (bortezomib and lenalidomide), and rapidly translated these agents from bench to bedside and FDA approval. The current proposal will define the molecular, functional, and therapeutic relevance of interactions of MM cells with accessory cells (BMSCs, osteoblasts, osteoclasts, and endothelial cells) in the BM milieu. Our central hypothesis is that the biological behavior of MM cells in the BM microenvironment is modulated by their interactions with individual BM accessory cells, and that the molecular and functional sequelae of these interactions represent potential therapeutic targets. To address this hypothesis, we will characterize the molecular contribution of individual cellular components of the BM microenvironment on MM cell proliferation, survival, and drug resistance (Specific Aim 1); validate the functional significance and therapeutic relevance of molecular events triggered in vitro by the interaction of MM cells with BM microenvironment (Specific Aim 2); and validate the therapeutic implications of targeting molecular events triggered by MM-BM microenvironment interactions in vivo (Specific Aim 3). Our studies will provide the framework for a new treatment paradigm targeting MM cell-BM accessory cell interactions to overcome drug resistance and improve patient outcome.